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Drug discovery for overcoming chronic kidney disease (CKD): new therapy for CKD by a (pro)renin-receptor-blocking decoy peptide Ichihara A; Sakoda M; Kurauchi-Mito A; Narita T; Kinouchi K; Itoh HJ Pharmacol Sci 2009[Jan]; 109 (1): 20-3Discovery of the (pro)renin receptor uncovered a novel function of renin/prorenin as the receptor ligands in addition to the enzyme and its precursor. The bindings of renin and prorenin to the (pro)renin receptor trigger two major pathways: the angiotensin II-dependent pathway as a result of the enzymatic activation of renin/prorenin and the angiotensin II-independent intracellular pathway involving hypertrophic, hyperplastic, and profibrotic signals. A specific blocker of the receptor was discovered through identification of the amino acid sequence of prorenin prosegment that binds to the receptor and leads to non-proteolytic conversion of prorenin to its active form. A peptide containing this sequence was found to block the binding of prorenin to its receptor. Its infusion in animal models of diabetes and low-renin hypertension significantly inhibited the development and progression of nephropathy, but (pro)renin receptor blockade had no benefit in the clipped kidney of 2K1C rats or rat models of high-renin hypertension. Since renin is still active without a (pro)renin receptor, (pro)renin-receptor blockade elicits a maximum benefit under low-renin conditions. Thus, (pro)renin-receptor blockade can be a useful therapy for chronic kidney disease with low renin levels in the plasma.|Animals[MESH]|Drug Discovery/*methods[MESH]|Humans[MESH]|Kidney Failure, Chronic/*drug therapy/physiopathology/prevention & control[MESH]|Models, Biological[MESH]|Peptides/chemical synthesis/pharmacology/*therapeutic use[MESH]|Prorenin Receptor[MESH]|Receptors, Cell Surface/*antagonists & inhibitors/physiology[MESH] |
